lignans and Neuroblastoma

The purpose of this research was to study whether verbenalin, an iridoid glucoside, and (+)-eudesmin, a furofuran lignan isolated from different plant families, can attenuate cell damage and death induced by 6-hydroxydopamine (6-OHDA) in human neuroblastoma SH-SY5Y cells.. SH-SY5Y cells were incubated with 6-OHDA (35 µM) for 1 day. Verbenalin and (+)-eudesmin were administrated with various concentrations (1, 2.5, 5, 10, 20, and 50 µM) one hour before the 6-OHDA treatment. After 1 day, cell viability and neuroprotective effect were investigated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Nitrosative stress was determined with measurements of nitric oxide (NO) and 3-nitrotyrosine (3-NT), a biomarker of peroxynitrite formation.. We observed that 6-OHDA declined viability and augmented LDH leakage in SH-SY5Y cells. MTT analyses showed that pretreatment with verbenalin and (+)-eudesmin markedly prevented the toxicity due to 6-OHDA (P < 0.05). Verbenalin and (+)-eudesmin suppressed LDH release induced by 6-OHDA (P < 0.01). Although 6-OHDA treatment produced no marked effects on NO levels, (+)-eudesmin at high concentrations (10-50 µM) markedly attenuated NO levels (P < 0.01). There was a significant increase in 3-NT levels with 6-OHDA exposure in cells. Pretreatment with verbenalin, but not (+)-eudesmin, diminished 3-NT levels at low concentrations (1-20 µM) and prevented the cytotoxic effect of 6-OHDA (P < 0.01).. These results indicated that verbenalin and (+)-eudesmin exert potent cytoprotective activities against cytotoxicity triggered by 6-OHDA in neuroblastoma cells. This is the first report demonstrating that verbenalin may act as a peroxynitrite scavenger.

Topics: Apoptosis; Cell Line, Tumor; Cell Survival; Humans; Lignans; Neuroblastoma; Neuroprotective Agents; Nitrosative Stress; Oxidopamine; Peroxynitrous Acid; Reactive Oxygen Species

Nine tetrahydrofuran lignans, including three undescribed spiro-lignans, were isolated from Isatis indigotica Fortune (Brassicaceae). Extensive spectroscopic analyses achieved the structure elucidation of these tetrahydrofuran lignans, and quantum chemical calculation combined with the MAE

Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Furans; Humans; Hydrogen Peroxide; Isatis; Lignans; Molecular Structure; Neuroblastoma

Seven lignans (1a/1b-2a/2b and 3-5), including six new compounds (1b, 2a/2b, 3-5), were isolated from the fruits of Crataegus pinnatifida. Their structures were elucidated by comprehensive spectroscopic analyses. Compounds 1b/1b-2a/2b were two pairs of enantiomers and the absolute configurations were determined by comparison of their experimental and calculated ECD spectra. Moreover, bioinformatics analysis suggested that more than a third of diseases were related to the nervous system. Therefore, all compounds were evaluated for neuroprotective effects toward human neuroblastoma SH-SY5Y cells injury induced by H

Topics: Crataegus; Fruit; Humans; Hydrogen Peroxide; Lignans; Molecular Structure; Neuroblastoma; Neuroprotective Agents

Oxidative stress and mitochondrial dysfunction contribute greatly to fluoride-induced cognitive impairment and behavioural disorders. Honokiol, a natural biphenolic compound, possesses antioxidant and mitochondrial protective properties. The present study investigated the protective actions of honokiol on NaF-elicited cognitive deficits and elucidated the possible mechanism of honokiol-mediated protection. The results demonstrated that honokiol administration markedly attenuated fluoride-induced cognitive impairments and neural/synaptic injury in mice. Moreover, honokiol elevated the activity and expression of SOD2 and promoted mtROS scavenging through Sirt3 activation in NaF-treated mice and SH-SY5Y cell lines. Meanwhile, honokiol substantially lowered mtROS production by enhancing Sirt3-mediated mitochondrial DNA (mtDNA) transcription, thereby leading to significant increases in ATP synthesis and complex I activity. Further studies revealed that honokiol activated AMPK and upregulated the PGC-1α and Sirt3 protein expression in vivo and in vitro. Intriguingly, the protective actions of honokiol on oxidative stress and mitochondrial dysfunction were abolished by AMPK shRNA or Sirt3 shRNA. Notably, AMPK knockdown prevented the increase in PGC-1α and Sirt3 expression induced by honokiol, while Sirt3 shRNA suppressed Sirt3 signaling without significant effects on p-AMPK and PGC-1α expression. In conclusion, our findings indicate that honokiol mitigates NaF-induced oxidative stress and mitochondrial dysfunction by regulating mtROS homeostasis, partly via the AMPK/PGC-1α/Sirt3 pathway, which ultimately contributes to neuronal/synaptic injury and cognitive deficits.

Topics: AMP-Activated Protein Kinases; Animals; Biphenyl Compounds; Cognition; Cognitive Dysfunction; DNA, Mitochondrial; Fluorides; Humans; Lignans; Mice; Mitochondria; Neuroblastoma; Oxidative Stress; RNA, Small Interfering; Sirtuin 3

Alzheimer's disease (AD) is a neurodegenerative disease, characterized by memory loss and cognitive deficits accompanied by neuronal damage and cholinergic disorders. Sesamol, a lignan component in sesame oil, has been proven to have neuroprotective effects. This research aimed to investigate the preventive effects of sesamol on scopolamine (SCOP)-induced cholinergic disorders in C57BL/6 mice. The mice were pretreated with sesamol (100 mg/kg/d, p.o.) for 30 days. Behavioral tests indicated that sesamol supplement prevented SCOP-induced cognitive deficits. Sesamol enhanced the expression of neurotrophic factors and postsynaptic density (PSD) in SCOP-treated mice, reversing neuronal damage and synaptic dysfunction. Importantly, sesamol could balance the cholinergic system by suppressing the AChE activity and increasing the ChAT activity and

Topics: Animals; Antioxidants; Cholinergic Agents; Cognition; Cognitive Dysfunction; Humans; Lignans; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Nerve Growth Factors; Neuroblastoma; Neurodegenerative Diseases; Neuroinflammatory Diseases; Neuroprotective Agents; Oxidative Stress; Scopolamine; Sesame Oil

Cerebral ischemia-reperfusion (CIR) is a common feature of ischemic stroke and is a major cause of disability and death among stroke patients worldwide. Phyllanthin, a lignin polyphenol, is known for its varied biological properties, although its protective effects against CIR have not been reported. We evaluated the neuroprotective property of phyllanthin against CIR as well as the involvement of the AMP-activated protein kinase/nuclear factor erythroid 2-related factor 2 (AMPK/Nrf2) and nuclear factor kappa B (NF-κB) signaling pathways. Experimental animals were divided into five groups: controls (sham-operated), CIR-induced by middle cerebral artery occlusion (MCAO), and CIR-induced and administered phyllanthin at 2.5, 5, and 10 mg/kg, respectively. We investigated neurological functions, various signaling genes, and inflammatory clues. The results of in vitro assays demonstrated that phyllanthin assertively improved cellular functions through abrogation of the Nrf2 pathway. In vivo, CIR rats demonstrated neurological function deficits, while ischemic severity was evidenced by the activation of neuroinflammatory cytokines and tissue oxidative stress. Moreover, the expression of apoptosis markers such as Bax, B-cell lymphoma (Bcl-2), caspase-3, COX-2, PGE2, and LOX-1 abruptly increased. Phyllanthin prevented brain dysfunction and cerebral edema, and protected brain integrity. Conversely, it improved antioxidative enzyme activity, abrogated inflammatory cytokines, and increased IL-10 in chemokines. Also, phyllanthin significantly reduced Nrf2 and AMPK levels, with reduced expression of NF-κB indicating that cross-talk between the NF-kB and Nrf2 pathways is activated in CIR. Phyllanthin rescues the ischemic brain by regulating cellular signaling, which supports its use for complications like CIR and associated injury.

Topics: Animals; Antioxidants; Cell Line, Tumor; Lignans; Neuroblastoma; Neuroprotective Agents; Rats; Rats, Wistar; Reperfusion Injury

Ten undescribed sesquineolignans (1-10), including four sesqui-norlignans (1-4), were isolated from the fruits of Crataegus pinnatifida. Their structures were determined by comprehensive spectroscopic analyses. All compounds were examined for their neuroprotective activities against H

Topics: Cell Line, Tumor; Cell Survival; China; Crataegus; Fruit; Humans; Lignans; Molecular Structure; Neuroblastoma; Neuroprotective Agents; Phytochemicals

Two pairs of diastereoisomers (1/2 and 3/4) were isolated from the fruits of Rubus idaeus L. (Rosaceae). Their structures were elucidated on the basis of extensive spectroscopic analyses. Then chiral-phase HPLC resolution gave 1a/1b-4a/4b. Their absolute configurations were determined by comparison of the experimental ECD with the calculated data. Moreover, all isolated compounds were investigated for the neuroprotective effects against H

Topics: Cell Line, Tumor; China; Fruit; Humans; Lignans; Molecular Structure; Neuroblastoma; Neuroprotective Agents; Phytochemicals; Rubus

Ailanthus altissima Swingle is a deciduous tree, belonging to the Simaroubaceae family. Phytochemical investigation of the root barks of A. altissima showed the presence of eight pairs of enantiomeric 8,4'-type oxyneolignans (1a/1b-8a/8b) including nine undescribed compounds (1b, 2a, 3a/3b, 4a/4b, 5b, 7b, 8a). Their structures were elucidated by comprehensive spectroscopic analyses, and their absolute configurations were determined by comparison of the experimental and quantum chemical calculations of electronic circular dichroism (ECD) curves. In addition, their neuroprotective effects against H

Topics: Ailanthus; Cell Line, Tumor; China; Humans; Hydrogen Peroxide; Lignans; Molecular Structure; Neuroblastoma; Neuroprotective Agents; Oxidative Stress; Phytochemicals; Plant Bark; Plant Roots; Stereoisomerism

The investigation of the ethanol extract of the seeds of Crataegus pinnatifida led to the isolation of seven new 8-O-4' type sesquineolignans crasesquineolignan A-G (1-7), along with a reported analogue, leptolepisol B (8). The chemical structures of these compounds were elucidated based on complex analysis of their MS, 1D and 2D NMR data. All the isolated compounds were tested for their neuroprotective effects against the damage of human neuroblastoma SH-SY5Y cells induced by H

Topics: Cell Line, Tumor; Crataegus; Humans; Hydrogen Peroxide; Lignans; Neuroblastoma; Neuroprotective Agents; Phytochemicals; Plant Extracts; Seeds

Five pairs of enantiomeric 8-O-4' neolignans (1a/1b-5a/5b), including seven new compounds (1a/1b, 2a, 3a, 4a/4b and 5b), were obtained from the fruits of Crataegus pinnatifida Bge. Their structures were determined by comprehensive spectroscopic analyses. The absolute configurations of the enantiomers were determined by comparison of the experimental ECD with the calculated data. Additionally, all the enantiomeric neolignans were evaluated for their neuroprotective activity against H

Topics: Cell Line, Tumor; Crataegus; Fruit; Humans; Lignans; Molecular Structure; Neuroblastoma; Neuroprotective Agents; Oxidative Stress; Phytochemicals; Stereoisomerism

Topics: Apoptosis; Autophagy; Biphenyl Compounds; Caspase 3; Cell Survival; Humans; Lignans; Neuroblastoma; Signal Transduction; Time Factors; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Neuroblastoma (NB) is a neuroendocrine tumor derived from neural crest cells. Approximately 90% of cases occur in children less than 5 years old. The amplification of MYCN correlates with high-risk neuroblastoma and patients with MYCN amplified showed poorer prognosis than those without MYCN amplification. In this study, three compounds isolated from Juniperus oblonga showed anti-proliferative activity against NB cell lines with and without tetracycline inducible MYCN over-expression which were identified as (-)-deoxypodophyllotoxin (1), (-)-matairesinol (2) and (+)-isocupressic acid (3). The effects of compounds 2 and 3 in NB cells included a decrease in NB cell viability and induction of apoptosis. Compound 1 was more effective in NB cells over-expressing MycN. Compound 1 also showed almost 2-fold induction of intracellular free calcium levels in M2(+) cells, which may indicate a different mechanism of action for this compound. Cytotoxicity studies against the human embryonic kidney cell (HEK-293) showed compounds 1, 2 and 3 were ineffective in the non-cancer cells at concentrations approximating their IC

Topics: Antineoplastic Agents; Carboxylic Acids; Cell Line, Tumor; Cell Survival; Child, Preschool; Diterpenes; Drugs, Chinese Herbal; Furans; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Inhibitory Concentration 50; Juniperus; Lignans; Molecular Structure; N-Myc Proto-Oncogene Protein; Neuroblastoma; Phytotherapy; Plant Extracts; Podophyllotoxin; Tetrahydronaphthalenes

Topics: Apoptosis; Cell Line, Tumor; Crataegus; Humans; Lignans; Molecular Structure; Neuroblastoma; Neuroprotective Agents; Seeds

Neuroblastoma is the most common form of childhood extracranial tumor and almost half of neuroblastoma cases occur in infants under two years old. Neuroblastoma accounts for ~6‑10% of childhood cancers and 15% of cancer‑associated childhood mortality. However, an effective treatment remains to be developed. Honokiol exhibits long‑lasting central muscle relaxation, anti‑inflammatory, antibacterial, antimicrobial, antiulcer, antioxidation, antiaging and antitumor effects. Honokiol has been previously demonstrated to kill neuroblastoma cells, however, the underlying mechanism of action remains unclear. The present study reports that honokiol inhibits the growth of neuroblastoma cells via upregulation of reactive oxygen species (ROS). MTT assays demonstrated that treatment of Neuro‑2a neuroblastoma cells with honokiol resulted in time‑ and dose‑dependent inhibition of cell proliferation, which was associated with upregulation of the protein expression of receptor‑interacting protein kinase 3 (RIP3), as demonstrated by western blot analysis. Furthermore, knockdown of RIP3 by small interfering RNA, or pharmacological inhibition of RIP3 by the RIP3 specific inhibitor necrosulfonamide, reversed honokiol‑induced loss of cell viability in Neuro‑2a cells. Importantly, honokiol significantly increased the intracellular ROS levels as determined by a 2',7'‑dichlorofluorescin diacetate assay, while ROS scavenger N‑acetyl cysteine significantly prevented the induction of ROS and RIP3 by honokiol. The results of the present study indicate that honokiol may suppress the growth of neuroblastoma Neuro‑2a cells, at least partially, through ROS‑mediated upregulation of RIP3.

Topics: Acetylcysteine; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Silencing; Humans; Lignans; Neuroblastoma; Reactive Oxygen Species; Receptor-Interacting Protein Serine-Threonine Kinases; RNA, Small Interfering; Time Factors; Up-Regulation

In children, neuroblastomas are the most common and deadly solid tumor. Our previous study showed that honokiol, a small-molecule polyphenol, can traverse the blood-brain barrier and kill neuroblastoma cells. In this study, we further investigated the mechanisms of honokiol-induced insults to neuroblastoma cells. Treatment of neuroblastoma neuro-2a cells with honokiol elevated the levels of microtubule-associated protein light chain 3 (LC3)-II and induced cell autophagy in time- and concentration-dependent manners. Interestingly, pretreatment with 3-methyladenine (3-MA), an inhibitor of autophagy, led to the simultaneous attenuation of honokiol-induced cell autophagy and apoptosis but did not influence cell necrosis. As to the mechanisms, exposure of neuro-2a cells to honokiol time-dependently decreased the amount of phosphatidylinositol 3-kinase (PI3K). Sequentially, honokiol downregulated phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) in neuro-2a cells. Furthermore, honokiol elevated the levels of glucose-regulated protein (GpR)78, an endoplasmic reticular stress (ERS)-associated protein, and amounts of intracellular reactive oxygen species (ROS). In contrast, reducing production of intracellular ROS using N-acetylcysteine, a scavenger of ROS, concurrently suppressed honokiol-induced cellular autophagy. Consequently, honokiol stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2. However, pretreatment of neuro-2a cells with PD98059, an inhibitor of ERK1/2, lowered honokiol-induced autophagy. The effects of honokiol on inducing autophagy and apoptosis of neuroblastoma cells were further confirmed using mouse neuroblastoma NB41A3 cells as our experimental model. Fascinatingly, treatment of neuroblastoma neuro-2a and NB41A3 cells with honokiol for 12 h did not affect cell autophagy or apoptosis but caused significant suppression of cell migration. Taken together, this study showed that honokiol can induce autophagy of neuroblastoma cells and consequent apoptosis through activating the PI3K/Akt/mTOR and ERS/ROS/ERK1/2 signaling pathways and suppressing cell migration. Thus, honokiol has potential for treating neuroblastomas.

Topics: Animals; Apoptosis; Autophagy; Biphenyl Compounds; Cell Line, Tumor; Cell Movement; Endoplasmic Reticulum Stress; Extracellular Signal-Regulated MAP Kinases; Humans; Lignans; Mice; Neuroblastoma; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases

The fruit of Schisandra chinensis (Turcz.) Baill, has been traditionally used in management of liver diseases and ageing associated neurodegeneration. The bioactive compound from this medicinal plant would be valuable for its potential use in prevention and treatment of Parkinson׳s disease.. The overall objective of the present study was to understand the neuroprotective effect of schisantherin A, a dibenzocyclooctadiene lignan from the fruit of S. chinensis (Turcz.) Baill, and to elucidate its underlying mechanism of action.. This study investigated the protective effect of schisantherin A against selective dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced neural damage in human neuroblastoma SH-SY5Y cells and zebrafish models. Oxidative stress and related signaling pathways underlying the neuroprotective effect were determined by multiple biochemical assays and Western blot.. Pretreatment with schisantherin A offered neuroprotection against 6-OHDA-induced SH-SY5Y cytotoxicity. Moreover, schisantherin A could prevent 6-OHDA-stimulated dopaminergic neuron loss in zebrafish. Our mechanistic study showed that schisantherin A can regulate intracellular ROS accumulation, and inhibit NO overproduction by down-regulating the over-expression of iNOS in 6-OHDA treated SH-SY5Y cells. Schisantherin A also protects against 6-OHDA-mediated activation of MAPKs, PI3K/Akt and GSK3β.. These findings demonstrate that schisantherin A may have potential therapeutic value for neurodegenerative diseases associated with abnormal oxidative stress such as Parkinson׳s disease.

Topics: Animals; Antiparkinson Agents; Cell Line, Tumor; Cyclooctanes; Dioxoles; Dopaminergic Neurons; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lignans; Neuroblastoma; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Oxidopamine; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Schisandra; Signal Transduction; Zebrafish

The potential protective effects of arctigenin on 1-methyl-4-phenylpyridinium ion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride-induced neurotoxicity were examined, and the results indicated that arctigenin could improve the movement behaviors and upregulate dopamine and γ-aminobutyric acid levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride-induced neurotoxicity mouse model. A further in vitro experiment showed that the pretreatment with arctigenin on cultured human neuroblastoma SH-SY5Y cells could obviously attenuate the decrease of cell survival rates caused by treatment with 1-methyl-4-phenylpyridinium ion by way of acting against cell apoptosis through the decrease of Bax/Bcl-2 and caspase-3, and by antioxidative action through reduction of the surplus reactive oxygen species production and downregulation of mitochondrial membrane potential. It is for the first time that a neuroprotective activity of arctigenin in both in vitro and in vivo experiments was reported, enlightening that arctigenin could be useful as a potential therapeutic agent for Parkinson's disease.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Apoptosis; bcl-2-Associated X Protein; Behavior, Animal; Brain; Cell Line, Tumor; Cell Survival; Dopamine; Furans; gamma-Aminobutyric Acid; Humans; Lignans; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; MPTP Poisoning; Neuroblastoma; Neuroprotective Agents; Neurotoxicity Syndromes; Parkinson Disease

Arctigenin (Arc) has been shown to act on scopolamine-induced memory deficit mice and to provide a neuroprotective effect on cultured cortical neurons from glutamate-induced neurodegeneration through mechanisms not completely defined. Here, we investigated the neuroprotective effect of Arc on H89-induced cell damage and its potential mechanisms in mouse cortical neurons and human SH-SY5Y neuroblastoma cells. We found that Arc prevented cell viability loss induced by H89 in human SH-SY5Y cells. Moreover, Arc reduced intracellular beta amyloid (Aβ) production induced by H89 in neurons and human SH-SY5Y cells, and Arc also inhibited the presenilin 1(PS1) protein level in neurons. In addition, neural apoptosis in both types of cells, inhibition of neurite outgrowth in human SH-SY5Y cells and reduction of synaptic marker synaptophysin (SYN) expression in neurons were also observed after H89 exposure. All these effects induced by H89 were markedly reversed by Arc treatment. Arc also significantly attenuated downregulation of the phosphorylation of CREB (p-CREB) induced by H89, which may contribute to the neuroprotective effects of Arc. These results demonstrated that Arc exerted the ability to protect neurons and SH-SY5Y cells against H89-induced cell injury via upregulation of p-CREB.

Topics: Animals; Cell Survival; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Furans; Humans; Lignans; Mice; Neuroblastoma; Neuroprotective Agents; Phosphorylation; Tumor Cells, Cultured

An efficient synthesis of honokiol with Suzuki-Miyaura cross coupling obtained an overall yield of 45%. The proposed approach successfully synthesized several structurally similar alkyl, alkenyl and alkynyl analogues, seven of which showed potential neuropreventive activity against MPP(+)-induced and CHP/TBHP oxidative stress induced neuroblastoma cell death.

Topics: Biphenyl Compounds; Catalysis; Cell Death; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Drug Design; Humans; Lignans; Models, Chemical; Neuroblastoma; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Time Factors

Neuroblastomas, an embryonic cancer of the sympathetic nervous system, often occur in young children. Honokiol, a small-molecule polyphenol, has multiple therapeutic effects and pharmacological activities. This study was designed to evaluate whether honokiol could pass through the blood-brain barrier (BBB) and induce death of neuroblastoma cells and its possible mechanisms. Primary cerebral endothelial cells (CECs) prepared from mouse brain capillaries were cultured at a high density for 4 days, and these cells formed compact morphologies and expressed the ZO-1 tight-junction protein. A permeability assay showed that the CEC-constructed barrier obstructed the passing of FITC-dextran. Analyses by high-performance liquid chromatography and the UV spectrum revealed that honokiol could traverse the CEC-built junction barrier and the BBB of ICR mice. Exposure of neuroblastoma neuro-2a cells and NB41A3 cells to honokiolinduced cell shrinkage and decreased cell viability. In parallel, honokiol selectively induced DNA fragmentation and cell apoptosis rather than cell necrosis. Sequential treatment of neuro-2a cells with honokiol increased the expression of the proapoptotic Bax protein and its translocation from the cytoplasm to mitochondria. Honokiol successively decreased the mitochondrial membrane potential but increased the release of cytochrome c from mitochondria. Consequently, honokiol induced cascade activation of caspases-9, -3, and -6. In comparison, reducing caspase-6 activity by Z-VEID-FMK, an inhibitor of caspase-6, simultaneously attenuated honokiol-induced DNA fragmentation and cell apoptosis. Taken together, this study showed that honokiol can pass through the BBB and induce apoptotic insults to neuroblastoma cells through a Bax-mitochondrion-cytochrome c-caspase protease pathway. Therefore, honokiol may be a potential candidate drug for treating brain tumors.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Blood-Brain Barrier; Brain Neoplasms; Caspases; Cell Line, Tumor; Cell Survival; Cells, Cultured; Cytochromes c; DNA Fragmentation; Endothelial Cells; Humans; Lignans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred ICR; Mitochondria; Neuroblastoma; Proto-Oncogene Proteins c-bcl-2; Tight Junctions

Two new tetrahydrofuran lignans, schiglaucin A and B (1-2), together with eight known analogues (3-10), were isolated from the stems of Schisandra glaucescens Diels. Their structures were elucidated on the basis of spectroscopic techniques (HRESIMS, UV, IR, NMR, and CD experiments). All of the compounds were tested for their neuroprotective activities against H₂O₂- and CoCl₂-induced cell injuries in SH-SY5Y cells, respectively. Compounds 1-10 showed significant neuroprotective effects against H₂O₂-induced SH-SY5Y cell death, while compounds 1-5 and 8-10 exhibited significant neuroprotective effects against CoCl₂-induced SH-SY5Y cell injury.

Topics: Cell Death; Cell Survival; Cobalt; Humans; Hydrogen Peroxide; Lignans; Molecular Structure; Neuroblastoma; Neuroprotective Agents; Plant Extracts; Plant Stems; Schisandra; Tumor Cells, Cultured

We investigated the cytotoxicity of six neolignans (1-6), which are similar in structure to furanocyclohexenone with an angular allyl group, in human neuroblastoma cell lines (IMR-32, LA-N-1, NB-39, SK-N-SH) and normal cells [human umbilical vein endothelial cells (HUVEC) and human dermal fibroblasts (HDF)] using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Two neolignans, ferrearin C (1) and 2, showed significant cytotoxicity in neuroblastoma cells. Typical morphologic features of apoptosis were observed for the ferrearin-type neolignans using Hoechst 33342, and apoptotic cytoplasmic membrane inversion was also induced by ferrearin-type neolignans in IMR-32. Furthermore, a Proteome Profiler Array showed that the ferrearin-type neolignans induced the marked expression of heme oxygenase-1 (HO-1). In a western blot analysis, ferrearin C (1) increased the level of Bax and reduced the level of survivin, indicating the activation of the mitochondrial pathway of apoptosis.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Cell Line; Cell Line, Tumor; Flow Cytometry; Heme Oxygenase-1; Humans; Inhibitor of Apoptosis Proteins; Lignans; Models, Biological; Molecular Structure; Neuroblastoma; Survivin

Advances in understanding the neurodegenerative pathologies are creating new opportunities for the development of neuroprotective therapies, such as antioxidant food factors, lifestyle modification and drugs. However, the biomarker by which the effect of the agent on neurodegeneration is determined is limited. We here address hexanoyl dopamine (HED), one of novel dopamine adducts derived from brain polyunsaturated acid, referring to its in vitro formation, potent toxicity to SH-SY5Y cells, and application to assess the neuroprotective effect of antioxidative food factors. Dopamine is a neurotransmitter, and its deficiency is a characterized feature in Parkinson's disease (PD); thus, HED provides a new insight into the understanding of dopamine biology and pathophysiology of PD and a novel biomarker for the assessment of neuroprotective therapies. We have established an analytical system for the detection of HED and its toxicity to the neuroblstoma cell line, SH-SY5Y cells. Here, we discuss the characteristics of the system and its applications to investigate the neuroprotective effect of several antioxidants that originate from food.

Topics: Antioxidants; Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Curcumin; Dioxoles; Dopamine; Humans; Lignans; Neuroblastoma; Parkinson Disease; Tandem Mass Spectrometry; Tocopherols; Tocotrienols; Xanthophylls

Lignans are natural phytochemicals which exhibit multiple pharmacological effects such as anti-inflammation, antivirus and anti-tumor activities. Whether they have effects on neural tissues and ion channels is still unknown. The effects of several arylnaphathalene lignans purified from Taiwania cryptomerioides on voltage-gated K(+) (Kv) channels in mouse neuroblastoma N2A cells were examined. These lignans included Taiwanin E, helioxanthin (HXT) and diphyllin. All lignans showed inhibitory effects on Kv channels and HXT was the most potent compound (IC(50)=1.7 μM). The mechanism of HXT block was further investigated. Its action was found to be extracellular but not intracellular. HXT accelerated current decay, caused a left-shift in steady-state inactivation curve but had no effect on voltage-dependence of activation. HXT block was unaffected by intracellular K(+) concentrations. Further, it did not affect ATP-sensitive K(+) channels. Our data therefore suggest that HXT is a potent and specific blocker of Kv channels, possibly with an inhibitory mechanism involving acceleration of slow inactivation.

Topics: Animals; Benzodioxoles; Cell Line, Tumor; Cupressaceae; Dioxolanes; Lignans; Mice; Neuroblastoma; Plant Extracts; Potassium Channel Blockers; Potassium Channels, Voltage-Gated

This study is to investigate the protective effect of (-) clausenamide against the neurotoxicity of okadaic acid in SH-SY5Y cell line, and injection beta-amyloid peptide25-35 (Abeta25-35) to the cerebral ventricle in ovariectomy (OVX) rats. MTT assay, LDH assay, and Hoechst 33258 staining were used to detect the effect of (-) clausenamide on the toxicity of okadaic acid in SH-SY5Y cell line. The animal model was induced by ovariectomized and injection of Abeta25-35 in the cerebroventricle of rats. The effect of (-) clausenamide on learning and memory deficiency was observed by step-through test. Electron microscope, Nissl body staining, and HE staining were used to examine the morphological changes in hippocampus and cerebral cortex neurons. Pretreatment of (-) clausenamide and LiCl decreased the rate of cell death from MTT, LDH release, and apoptosis from Hoechst 33258 staining in SH-SY5Y cell line. The step-through tests showed (-) clausenamide could improve the ability of learning and memory. The Nissl body staining and HE staining experiments also showed the neuroprotective effects of (-) clausenamide on the neurons of hippocampus and cerebral cortex. (-) Clausenamide has the protective effects against the neurotoxicity induced by okadaic acid and Abeta25-35.

Topics: Amyloid beta-Peptides; Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Cerebral Cortex; Clausena; Drugs, Chinese Herbal; Female; Hippocampus; Humans; L-Lactate Dehydrogenase; Lactams; Learning; Lignans; Memory Disorders; Neuroblastoma; Neurons; Neuroprotective Agents; Okadaic Acid; Ovariectomy; Peptide Fragments; Plants, Medicinal; Rats; Rats, Sprague-Dawley

We examined the intracellular Ca(2+) response in primary cultured rat cortical neurons and human neuroblastoma SH-SY5Y cells by Fluo 3 fluorescence imaging analysis. In these two kinds of neuronal cells, honokiol and magnolol increased cytoplasmic free Ca(2+) with a characteristic lag phase. The cytoplasmic free Ca(2+) increase was independent of extracellular Ca(2+), but dependent on activation of phospholipase C and inositol 1,4,5-triphosphate (IP(3)) receptors. These results suggest that honokiol and magnolol increase cytoplasmic free Ca(2+) through a phospholipase C-mediated pathway, and that the release of Ca(2+) from intracellular stores mainly contributes to the increase in cytoplasmic free Ca(2+). Thus, honokiol and magnolol may be involved in a new activation mechanism closely associated with intracellular Ca(2+) mobilization.

Topics: Animals; Biphenyl Compounds; Calcium; Cell Line, Tumor; Cells, Cultured; Cerebral Cortex; Female; Humans; Lignans; Neuroblastoma; Neurons; Pregnancy; Rats; Rats, Sprague-Dawley